Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis
Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis
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DOI：
10.4049/jimmunol.1601649
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发表时间：
2017-01-15
影响因子：
4.4
通讯作者：
Bar-Or, Amit
中科院分区：
文献类型：
--
作者：
Li, Rui;Rezk, Ayman;Bar-Or, Amit
被批准用于治疗复发缓解型多发性硬化症患者的富马酸二甲酯 (DMF) 的治疗作用模式尚不完全清楚。最近，我们和其他人证明，不同 B 细胞亚群的独立于抗体的功能对于介导多发性硬化症 (MS) 复发疾病活动非常重要。我们的目的是测试 DMF 是否以及如何影响 MS 患者中与疾病相关的 B 细胞亚群的表型和功能反应。在开始 DMF 治疗之前和之后连续从复发缓解型 MS 患者中获得高质量的 PBMC。多参数流式细胞术用于监测不同 B 细胞亚群的表型和功能反应概况。 DMF 处理后 B 细胞总数减少，很大程度上反映了循环成熟/分化（但不是未成熟过渡）B 细胞的损失。在成熟 B 细胞库中，DMF 对记忆的影响比幼稚 B 细胞更大。与这些体内效应一致，DMF 体外治疗通过诱导细胞凋亡介导显着降低成熟（但不是过渡 B 细胞）的存活率。尽管 DMF 治疗（体内和体外）对 B 细胞 IL-10 表达的影响最小，但它强烈降低了 B 细胞 GM-CSF、IL-6 和 TNF-α 的表达，导致 B 细胞反应谱发生显着的抗炎转变。 DMF 介导的 B 细胞促炎细胞因子反应的减少进一步与存活 B 细胞中 STAT5/6 和 NF-κ B 磷酸化的减少有关。总之，这些数据暗示了 DMF 可能通过改变促炎和抗炎 B 细胞反应之间的平衡来调节 MS 疾病活动的新机制。
The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL-10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF-alpha, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-kappa B in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro-and anti-inflammatory B cell responses.